Definity

SIDE EFFECTS

A total of 1716 subjects were evaluated in pre-market clinical trials of activated
DEFINITY®. In this group, 1063 (61.9%) were male and 653 (38.1%) were female,
1328 (77.4%) were White, 258 (15.0%) were Black, 74 (4.3%) were Hispanic, and
56 (3.3%) were classified as other racial or ethnic groups. The mean age was
56.1 years (range 18 to 93). Of these, 144 (8.4%) had at least one adverse reaction
(Table 6.1). There were 26 serious adverse events and 15 (0.9%) subjects discontinued
because of an adverse event.

Deaths and Serious Adverse Events

Among the 1716 activated DEFINITY® patients, 19 (1.1%) suffered serious
cardiopulmonary adverse events including eight deaths. The deaths occurred several
days after activated DEFINITY® administration and appeared to be related
to the course of underlying disease. Of the 11 other serious adverse events,
which appeared within days of the drug administration (2-15 days), all appeared
to be a progression underlying cardiac and noncardiac disease. However, a role
for DEFINITY® in the initiation or course of these adverse events cannot
be ruled out.

Discontinuations

There were 15 discontinuations reported with a mean age of 41.5 years. Nine
of these patients were discontinued after the first injection. One patient experienced
a hypersensitivity reaction with urticaria and pruritus and all the other patients
experienced dizziness, chest pain, dyspnea or back pain. These adverse reactions
appeared within minutes (1 – 15 min) of the drug administration and were of
moderate intensity resolving usually without treatment within minutes or hours
after onset.

For all adverse reactions, the overall incidence of adverse experiences was
similar for the < 65 year age group and the > 65 year age group, similar
in males and in females, similar among all racial or ethnic groups, and similar
for bolus and infusion dosing. Table 6.1 summarizes the most common adverse
reactions.

Postmarketing Experience

In a prospective, multicenter, open-labelregistry of 1053 patients receiving
DEFINITY® in routine clinical practice, heart rate, respiratory rate, and
pulse oximetry were monitored for 30 minutes after DEFINITY® administration.
No deaths or serious adverse reactions were reported, suggesting that these
reactions are unlikely to occur at a rate of more than 0.3% when DEFINITY®
is used according to recommendations.

The following adverse reactions have been identified during the post-marketing
use of perflutren-containing microsphere products. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always possible
to reliably estimate their frequency or establish a causal relationship to drug
exposure.